Mammalian pancreas is a storehouse of digestive enzymes the action of which, if turned against the organ, can have disastrous consequences. For this reason, the acinar cells of the pancreas possess a series of built-in, physiologic mechanisms to protect themselves against the effects of their own digestive enzymes. The most important of these protective mechanisms is the presence of potent inhibitors which can readily inactivate active proteinases that may arise intracellularly through accidental activation of the proenzymes. Nonetheless, evidence is growing that intracellular activation of proenzymes to active proteinases is a primary factor in the pathogenesis of both acute and chronic types of pancreatitis. The type and severity of the process would be determined, in any particular instance, by the balance, at that particular point in time, between the amount of active proteinases formed and the amount of available inhibitors. While much is known about the physiochemical properties, the specificity and the mechanism of action of the pancreas proteinase inhibitors, very little information is available about the factors which control their content in the organ. In the research proposed in this application we plan, 1) to measure the inhibitor content in the pancreas of inbred strains of mice and rats in order to identify strains with "low" endogenous contents, 2) to investigate whether the inhibitor content is influenced by age, sex and dietary regimen, 3) to correlate the inhibitor content with the extent of pancreatic pathology elicited by known pancreatotoxic agents, and 4) to study the modality of transmission and expression of the "low" gene. We shall pursue these studies by using, among other procedures, affinity chromatography and electrophoresis for the separation of the inhibitors; incorporation of labeled precursors to study their synthesis; experimental diets to study their effects on the inhibitors; and mating experiments.